Meg Rivers is the former senior editor for 

Meg Rivers

Cell therapies are a hot topic in the bio/pharma industry today. In this episode of the Drug Solutions Podcast, Meg Rivers, senior editor, Andrew Scharenberg, CEO, Umoja Biopharma, and Ryan Crisman, co-founder and chief technical officer, Umoja Biopharma, discuss:

The greatest advancements in cell therapy to date

The biggest trends in cell therapy development

The pros and cons of developing cell and gene therapies

In the discussion, one thing that came up a few times was that one of the major challenges in developing cell therapy is retention. This issue, according to the speakers, has led to the current trend for some biopharma companies to insource development rather than outsource to contract development and manufacturing organizations (CDMOs). The speakers also discussed scale up vs. scale out and various challenges and opportunities for autologous and allogeneic therapies.

 is the CEO of Umoja Biopharma, an MPM portfolio company. He also serves as an executive partner at MPM Capital and chairs the scientific advisory boards at Generation Bio, Genti Bio, and Alpine Immune Sciences. Prior to founding Umoja, Scharenberg co-directed the program in cell and gene therapy at Seattle Children’s Research Institute, working to translate cell and gene therapies for the treatment of inherited immunologic and blood diseases. This work led to the development of a program in engineered regulatory T-cells, partnered with Casebia Therapeutics, for the purpose of developing gene-edited cell therapeutics for type 1 diabetes and other inflammatory diseases. Previously, he was the chief scientific officer of Cellectis Therapeutics, where he initiated the development of an allogeneic CAR T-cell platform, and was the co-founder of Pregenen Inc., a gene-editing and cell-signaling technology company that was acquired by bluebird bio in 2014.

PhD, is the co-founder and chief technical officer of Umoja Biopharma. Before starting Umoja in 2019, Crisman served as the executive director for the Gates biomanufacturing facility, where he was responsible for building out and staffing this protein and cell therapy CDMO. He was instrumental in growing the facility’s current good manufacturing practice capabilities and delivering many first-in-human therapeutic products to patients. While at Juno Therapeutics, Crisman led the JCAR017 chemistry, manufacturing, and controls program and was the head of late-stage process development. He has also held scientific leadership positions at Zymogenetics and CMC Biologics.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Podcasts

Experts from Umoja Biopharma dive into cell therapy development in this episode of the Drug Solutions Podcast, including the greatest advancements in cell therapy to date, areas for improvement, the biggest trends in cell therapy development, and retention as a pain point. 

Drug Solutions Podcast: Cell Therapy Development: Advances, Trends, and the Challenge of Retention

In this exclusive Drug Digest video interview, Meg Rivers and Felicity Thomas, 

editors, interview experts in sterilization and aseptic processing. Alex Van Hagen of Watson-Marlow Fluid Technology Solutions discusses how to approach selecting sterilization methods, installation of aseptic machinery, how single-use technology factors into aseptic processing, and areas for improved automation. In a quick-fire interview, Hamish Hogg of Cherwell Laboratories talks about the eagerly anticipated publication of the revised EU GMP Annex 1 guidance, potentially problematic aspects of the revised guidance, and tips and tricks for companies to ensure compliance.

 is a molecular biologist by training and the current North UK life sciences sector specialist for Watson-Marlow Fluid Technology Solutions. In this position, Alex provides experience-based consultation to the life sciences sector, taking each project from cradle to gate. Previously, Alex worked in academic research centered on producing sustainable microbial cell factories for the production of fossil-fuel-based chemicals using renewable carbon sources, and his work has been presented internationally. In addition, Alex has been a guest lecturer at bioscience continued professional development courses within the UK and sits on an industry expert liaison panel at the University of Lincoln.

 has been the microbiology product specialist at Cherwell Laboratories since January 2019. He has a background as a biomedical scientist for the NHS in microbiology. Later, he expanded his career into medical devices companies, delivering technical support to end users and training to the internal and external corporate teams and customers.

This episode of Drug Digest is sponsored by:

Drug Digest is a tech talk video series with the 

 editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

Automating pharma and biopharma processes

Videos

Pharmaceutical Technology editors interview aseptic and sterilization experts from Watson-Marlow Fluid Technology Solutions and Cherwell—diving into sterilization, aseptic processing, and the revised EU GMP Annex 1 guidance.

Drug Digest: Sterilization’s Horizon: Improving Automation, Single-Use Technologies, and Annex 1

In what instances should organizations outsource vs. insource? Determining the right outsourcing strategy is key to limit unnecessary costs, maintain output and turnaround times, and enable continued flexibility. In part one of this outsourcing series, Meg Rivers, senior editor, and John Koleng, VP of product development and manufacturing for TFF Pharmaceuticals, discuss:

What the biopharma industry currently tends to outsource

Outsourcing strategies the biopharma industry should be utilizing

Internal tasks the biopharma industry should consider outsourcing more in development and manufacturing

What the biopharma industry should reconsider outsourcing and instead perform in-house

What organizations are choosing not to outsource and why

Curia is a global contract research, development, and manufacturing organization offering products and services across the drug development spectrum to help their partners turn ideas into real-world impact—from curiosity to cure.

John Koleng, PhD, VP of Product Development and Manufacturing, TFF Pharmaceuticals:

 Koleng has co-founded several life sciences development and industrialization consultancies focused on product development, manufacturing, scale up, commercialization, and supply chain management. He has more than 20 years of experience in the pharmaceutical industry, including more than 10 years as a consultant. Koleng has been a founding member of three drug development companies that are actively developing new products. He has a diverse range of drug development experience from formulation to route of administration. He has published numerous scientific research articles and is an inventor on 16 issued US patents and pending patent applications. Koleng has worked with TFF Pharmaceuticals as a consultant and is an inventor on several provisional patent applications filed on behalf of TFF. Prior to his consulting career, Koleng was a founding member and served in various roles at PharmaForm before the company was sold to Akela Pharma, Inc. in 2007. John Koleng, Ph.D., R.Ph., VP of Product Development and Manufacturing at TFF Pharmaceuticals has a BS degree in Pharmacy (1994), and a PhD in Pharmaceutics (2002), both from the University of Texas at Austin where he currently holds an adjunct assistant professor of pharmaceutics appointment and serves on the UT College of Pharmacy Dean’s Advisory Council. He is a registered pharmacist.

In this episode of the Drug Solutions Podcast, John Koleng, VP of product development and manufacturing for TFF Pharmaceuticals shares outsourcing strategies in biopharma.

Drug Solutions Podcast: Outsourcing vs. Insourcing in Biopharma: Determining the Best Strategy: Part 1

In this exclusive Drug Digest video, Meg Rivers and Feliza Mirasol interview experts in cell and gene therapies and antibody-drug conjugates. Specifically, they discuss the factors that could influence an organization to pursue specific biomolecules for development; key considerations for scalability; capacity issues; trends; chemistry manufacturing and controls; and how to ensure consistency and reproducibility.

Lisa McDermott, Director of Process and Analytical Development Global Contract Manufacturing Services, MilliporeSigma, the US and Canadian Life Science business of Merck KGaA Darmstadt, Germany

: Lisa McDermott is the director of the process and analytical development department at MilliporeSigma in St. Louis, Mo., which is responsible for the development and transfer of custom projects into GMP manufacturing and testing. Her previous background includes 17 years with Monsanto as a synthetic organic chemist working on both agricultural and pharmaceutical projects, followed by seven years at Pfizer with a focus on determining analytical control strategies for GMP success. Over McDermott’s 30 years of experience in synthetic and analytical sciences, she has had the opportunity to contribute to many projects, ranging from discovery to full commercial.

Jasna Curak, Global Quality and External Collaboration Manager, Hoffmann-La Roche Ltd

: Jasna Curak is part of Roche Global Compliance and External Collaboration; regulatory intelligence for ATMPs; GMP considerations; currently working with ISPE ATMP community of practice; active in drafting position papers; and is a commenting lead for the global regulatory landscape. Previously, she was in production management in large-scale manufacturing facilities for vaccine manufacturing and a GMP maintenance lead, supporting a reliable and robust process integrated with strong quality infrastructure. She holds a master’s degree in molecular genetics from the University of Toronto, and a bachelor’s degree in biochemistry, molecular biology from McMaster University, Canada.

Welcome to this episode of Drug Digest, a tech talk with the 

 editors, who discuss with experts the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

In this exclusive Drug Digest video, experts from Roche and MilliporeSigma divulge factors that could influence an organization to pursue specific biomolecules for development.

Drug Digest: Development and Scalability of ADCs and CGTs

Just how important is training for aseptic processing? Human error is one of the biggest pitfalls for contamination in aseptic processing, and the proper training of staff continues to be of the utmost importance. In this Drug Solutions Podcast episode, Patrick Nieuwenhuizen, director senior consultant, PharmaLex, shares how important training is for aseptic processing along with:

The differences in aseptic processing for small and large molecules

How single-use technologies impact aseptic processing

How aseptic processing can be better automated

, director senior consultant for PharmaLex Ireland, is a quality professional with a microbiology and sterile manufacturing background with more than 25 years of experience in the pharmaceutical industry. He worked for several global pharmaceutical and biotechnology companies across a variety of platforms, including biologics, sterile fil-finish, and solid oral dose. In addition, Patrick is a qualified lead auditor and SME in quality control, sterility assurance, new facility design/upgrade, and risk facilitator for quality risk management.

In this episode of the Drug Solutions Podcast, Meg Rivers, senior editor, discusses the importance of proper training for aseptic processing with Patrick Nieuwenhuizen, director senior consultant, PharmaLex.

Drug Solutions Podcast: The Criticality of Training in Aseptic Processing

Packaging sterile drug products into sterilized containers via sterilization or aseptic processing continues to be both an absolute necessity and a challenge for the bio/pharmaceutical industry. But where there are challenges, there is room for innovation as well as room to grow.

“Aseptic processing is one of the most challenging manufacturing processes in pharmaceutical development,” says Robert W. Lee, PhD, president, CDMO division, Lubrizol Life Science Health, a contract development and manufacturing organization (CDMO) located in Bethlehem, Pa. and provider of clinical and commercial aseptic processing. “Sterile is sterile. It is binary.”

One of the reasons aseptic processing, specifically, is so challenging is due to a lack of proper training as well as a lack of comprehensive understanding of the techniques. This can then lead to regulatory intervention.

“In aseptic processing, a lack of understanding of the importance of aseptic techniques and one’s impact on the environment can lead to an array of complications and compliance issues,” says Simren Ahmadi, quality specialist, GMP, Lubrizol Life Science Health. “For example, just last year, FDA issued 25 483 observation forms in relation to aseptic processing. Virtually, all these observations were regarding poor aseptic operational practices that were put in place by the facilities.”

According to Ahmadi, to adopt better aseptic practices and minimize regulatory observations, organizations must change how they view aseptic processing. Namely, to look at it not as an operation, but as a culture.

“When a facility adopts an aseptic culture, personnel begin to understand the ‘why’ behind aseptic processing and their impact on the environment. Explaining that aseptic techniques and behaviors are critical to avoid contamination and produce a sterile product for a patient while illustrating the impact one has on the environment enables personnel to understand why good aseptic technique is so important,” continues Ahmadi. “This promotes more comprehensive risk assessments, validations, qualifications, etc. by taking aseptic processing into consideration, which in turn identifies weak areas of a process before complications or compliance issues arise. Additionally, promoting an aseptic culture allows personnel to develop an audit mindset and know what to look for when it comes to aseptic processing. Personnel can continuously look for areas for improvement through their daily job functions or by simply walking on the floor and have any compliance issues addressed internally.”

Nonetheless, whether an organization views aseptic processing and sterilization as a culture or simply as a necessary step in the manufacturing process, the need for either isn’t up for debate.

“Sterility is an obligatory critical quality attribute for parenteral preparations; sterility cannot be assured by testing, but by use of well-designed, validated, and controlled manufacturing processes. Most modern therapeutics are parenteral preparations that are not suitable for terminal sterilization; instead, aseptic processing, whenever feasible, in combination with sterile filtration, has to be pursued,” says Hanns-Christian Mahler, CEO, ten23 health, a Switzerland-based CDMO with a specialty in the development and sterile manufacture of complex pharmaceuticals, such as biologics.

To have sterile end products, environmental controls must be in place. Quality assurance (QA) departments have their work cut out for them to perform risk assessments. Many processes must be established and standardized, and all employees must follow those processes faithfully.

“[QA] departments ensure aseptic processing will work as intended by performing risk assessments on the locations, methods, equipment, and frequency for the aseptic processing that will be conducted,” says Christopher DeHart, director of quality, Lubrizol Life Science Health. “In-depth quality risk assessments identify the risks involved with the aseptic process to be conducted and determine what controls need to be put in place to minimize these risks.”

DeHart breaks down these controls further:

: This should include room classifications, HEPA filters, first air, and airlocks.

: Working in conjunction with the facility, this includes monitoring the movement of the airflow, pressures, temperature, and humidity in real-time. This ensures the HEPA filters and airlocks are working as intended.

: To minimize the risk of microbial contamination, procedures and training programs should be in place so that aseptic techniques are understood and followed. These procedures should cover gowning, personnel/material/equipment flow, viable and non-viable sampling, reading plates, autoclaving, cleaning, and more.

Rainer Glöckler, head of new technologies, swissfillon—a ten23 health company that offers a range of services for sterile filling and finish of liquid active ingredients—breaks down environmental controls into three relevant categories:

: To ensure aseptic conditions of surfaces in the isolator, rodac plates are required; active air samples are needed to identify any living contaminant; passive air samples (settle plates) identify any particle in the laminar-air stream; and lastly, continuous particle measurement and fingertip end-of-batch tests are performed on all gloves installed on the isolator.

: Rodac plates are used to ensure aseptic conditions of surfaces in the cleanroom; active air samples are used to identify any living contaminants in the air; and continuous particle measurement is also performed.

: This includes a full routine control for particles, bio-contaminants, chemicals, and conductivity for water for injection.

Joerg Zimmermann, VP of Vetter Development Service External Affairs, Vetter Pharma-Fertigung GmbH & Co KG—a CDMO specializing in the fill/finish of sterile injectables and headquartered in Ravensburg, Germany—stresses the importance of a functioning cleanroom system.

“Before we get to the aseptic operation, we must first ensure that we have a functioning cleanroom system that provides a controlled environment for safe production. This includes tight controls on temperature, humidity, and differential pressure,” says Zimmermann. “Of utmost importance is airflow management to minimize the contamination risk. Air flows are visualized during the qualification of the cleanrooms to ensure unidirectional flow from the ceiling to the floor, and from the core filling area to the background. This needs to be done in static and dynamic conditions.”

Another aspect that should be noted is the importance of a sterile, Grade A, ISO 5 environment.

“Aseptic processing should be executed in a classified space with minimum characteristics for particulate and microbial control, consistent with ISO 5,” adds Kenneth Laderman, PhD, manufacturing director, Eurofins BioPharma Product Testing, a laboratory that supports small batch sterile GMP manufacturing in San Diego, Calif. “Maintaining this classification will require a routine cleaning and environmental monitoring program as well as controls over gowning, material movement, and personnel movement.”

Lee adds that, in addition to an ISO 5 environment, it’s also acceptable to use a fully closed process in an ISO 7 environment. This is where the entire product contact pathway is sterilized using steam-in-place methodology. Afterward, sterile API and sterile-filtered excipients are added aseptically to the closed system and the remainder of the process is conducted aseptically.

, Eurofins BioPharma Product Testing, Lubrizol, and ten23 health confirmed using single-use technologies in some of their aseptic processes. As with most things, there are both benefits and risks in doing so.

“Single-use systems [SUS] are advantageous, as they reduce the need for cleaning validation/verification activities for your process,” says DeHart. “In addition, the materials come certified sterile, reducing the need for a validated autoclave cycle for your processing equipment. In terms of a CDMO business model, the cost of the [SUS] can be passed to the client, enabling a cost-effective way to provide sterile manufacturing activities.”

Laderman states that Eurofins utilizes single-use technology for many product contact surfaces.

“As a CDMO, single-use technology facilitates the processing of multiple APIs within the same facility,” says Laderman. “In the absence of this technology, it would be necessary to execute a new cleaning validation for each molecule introduced into the manufacturing suite. By maintaining a single-use isolated system, the process is streamlined, decreasing time for project execution as well as turnaround time.”

According to Lee, Lubrizol uses SUS for small-volume sterile solution processing because this technology provides sterility assurance and flexibility as well as saves time. Lee adds that while SUS can be expensive, avoiding cleaning validation can lead to cost savings, depending on the application.

Meanwhile, Mahler at ten23 health states that the company uses single-use technologies for compounding/formulation down to the filling needle.

“[SUS] offer various advantages from a pharmaceutical perspective, including avoiding the risk for cross-contamination and avoiding related cleaning validation activities,” says Mahler. “However, [SUS] are a significant concern to us from a sustainability perspective, and we believe that biopharmaceutical solution providers should research new, more sustainable options.”

Companies should consider the following when using (or considering using) SUS in aseptic processing, according to Lee:

Are the materials of construction compatible with the API?

Depending on the complexity of the process as well as the product, SUS may not be advantageous, or a hybrid approach may be more ideal.

What are the lead times for materials? This can be anywhere from eight weeks to one year.

Single-use technologies and SUS seem to have simplified processes and provided an alternative approach to more traditional methods in the realm of aseptic processing and sterilization. But one of the key disadvantageous is the supply chain. Similar to Lee, Zimmermann shares that recent shortages related to the pandemic have revealed that when a single-use component, for example, isn’t available, production comes to a stop.

“There are some products where everything in compounding and in the liquid path is single-use, and we have others where it makes more sense to do a hybrid approach, with only the tubing and the filters being disposables,” says Zimmermann. “One thing that most people are not aware of is that the capacity for gamma-radiation, the method of choice for most [SUS], is under extreme pressure. This is causing companies to reconsider the processes on a strategic level. Another aspect that is coming into greater focus is the waste management of [SUS]. At the moment, the standard of disposal is incineration, which is not the most sustainable method.”

The greatest risk in aseptic processing is, of course, contamination, which can lead to a possible rejection of a batch, loss in revenue, product shortages, etc. And what is the greatest risk for contamination? People.

Both Zimmermann and Mahler state that the highest risk in aseptic processing comes from operators. Intense training can help to avoid contamination along with proper, sterilized gowns and testing the operators.

Laderman adds that well-designed systems for cleaning and air handling will minimize the risk as well as gowning procedures and training of personnel. Eurofins BioPharma Product Testing, specifically, uses a robotic, gloveless isolator to limit the product’s exposure to the operator.

In addition to the inherent risks that humans pose, there are other avenues leading to contamination. Potential causes for contamination, according to Ahmadi, can be anything from poor aseptic technique to equipment.

“[A] facility must have robust validations, qualifications, risk assessments, investigations, etc., as well as a robust aseptic techniques training program. These documents and programs must also be periodically reviewed to ensure they remain compliant,” Ahmadi says. “An organization must also ensure the facility design of critical areas can be easily cleaned and that personnel have the room and means to work aseptically. Additionally, [QA] should maintain a presence on the floor to promote good aseptic techniques and conduct walkthroughs of critical areas to ensure the facility is in good order and personnel are practicing good aseptic techniques.”

Like any part of the manufacturing process, aseptic processing has room to improve automation and has made significant progress in recent years.

“Automation requires flexibility, both in scale and duration of the function, while limiting the need for direct contact with the operators,” says Laderman. “Most automated systems are iterative by nature, as consumables utilized by the process will need to be resupplied. Decreasing the frequency of the resupply will minimize the chances for contamination.”

Laderman shares that Eurofins BioPharma Product Testing utilizes an automated robotic filler, which offers the lowest levels of extraneous particulate matter and the highest of sterility assurance. However, it’s dependent on the standardized nested vials and caps. Laderman believes that automation will continue to improve and be more readily adopted once additional vial types and sizes are available in standardized formats.

Similarly, when asked about opportunities for improved automation, Zimmermann points to the use of robots.

“Whatever can be automated, should be automated,” says Zimmermann. “The use of robots in cleanroom settings is increasing and constantly adding new tasks executed by robots. For us, this is not new, as we have been using robots since 1994. However, on new developments like the Flexi-cell that we are progressing with a partner, the robot does three distinct operations: set-up of the fill-line, the filling and stoppering process, and environmental monitoring. This makes the aseptic operation less risky and more robust. Automated environmental monitoring is considered for even more applications, but also remote troubleshooting via robot arms is being considered as well.”

Glöckler, on the other hand, looks to filling equipment without any glove intervention during aseptic processing as an area of improved automation. While the risk of contamination may be lessened, Glöckler adds that any problem in the isolator has the potential to impact process performance.

“Continuous online particle and bioburden testing replacing Settle plates, active air, and continuous particle measurement are in a development stage but still not accepted by authorities,” says Glöckler.

“Aseptic processing is better automated in that there is less human contact with the product, significantly lowering the possibility of contamination,” says Ahmadi, weighing in on the aseptic processing automation. “Automated aseptic processing removes the need for an operator to have close contact with the product and minimizes the number of operators needed in and out of critical areas. However, if automated aseptic processing is utilized, additional controls need to be put in place to ensure the equipment remains sterile. These controls include intervention procedures, cleaning validations, maintenance, etc. Aseptic processing is also better automated because it can produce more products in a shorter amount of time and minimizes the number of materials that need to be autoclaved. However, if the equipment is not functioning properly, there will be a loss of revenue in downtime.”

While we can’t banish humans entirely from the process floor, minimizing the risk associated with their presence is a major goal. Where the aseptic processing industry goes next, only time will tell. But it seems that single-use technologies and robotics will play a role in what’s on the horizon.

Pharmaceutical Technology, Pharmaceutical Technology Europe

Vol. 46, No. 6
June 2022
Pages: 16–18, 21

When referring to this article, please cite it as M. Rivers, “Automating Aseptic Processing Reduces Contamination Risk,” 

Articles

Industry experts discuss the need for stricter environmental controls, whether to incorporate single-use technologies, and areas for improved automation.  